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CLINICAL  METABOLISM 

THE   BASAL  METABOLIC  RATE  IN  EXOPH- 

THALMIC  GOITRE  (1917  CASES)  WITH 

A  BRIEF  DESCRIPTION  OF  THE 

TECHNIC  USED  AT  THE 

MAYO  CLINIC 


THE  EFFECT  OF  THE  SUBCUTANEOUS  IN- 

JECTION  OF  ADRENALIN  CHLORID  ON 

THE  HEAT  PRODUCTION,  BLOOD 

PRESSURE  AND  PULSE 

RATE  IN  MAN 


BY 

IRENE  SANDIFORD 
A  THESIS 

Submitted  to  the  Faculty  of  the  Graduate  School  of  the  University 

of  Minnesota  in  partial  fulfillment  of  the  requirements 

for  the  Degree  of  Doctor  ot  Philosophy 

1919 


\Aa^ 


N'^ 


THE   BASAL  METABOLIC   RATE    IN   EXOPHTHALMIC 
GOITRE  (1917  CASES)  WITH  A  BRIEF  DESCRIP- 
TION OF  THE   TECHNIC  USED  AT 
THE  MAYO  CLINIC 

Irene  Sandiford,  Ph.D. 
Mayo  Foundation,  University  of  Minnesota,  Rochester,  Minnesota 
''In  each  mammal  there  is  a  basal  metabolism"  (19)      By 
the  term  "basal  metabolism"  or  better,  -  basal  metabolic  rate  '•' 
of  an  organism  is  meant  the  minimal  heat  production  of  that 
organism,  measured  from  twelve  to  eighteen  hours  after  the 
ingestion  of  food  and  with  the  organism  at  complete  muscular 
rest.    This  minimal  heat  production  may  be  determined  directly 
by  actual  measurement  by  means  of  a  calorimeter,  or  indirectly 
by  calculating  the  heat  production  from  an  analysis  of  the  end 
products  which  result  from  oxidation  within  the  organism    or 
specifically,  from  the  amount  of  oxygen  used  and  the  correspond- 
ing amount  of  carbon  dioxid  produced,  together  with  the  total 
nitrogen  eliminated  in  the  urine  (although,  for  clinical  work  the 
urinary  nitrogen  may  be  neglected). 

The  experimental  work  of  Lavoisier  (17)  marks  the  begin- 
ning of  researches  on  metabolism,  and  to  him  belongs  the  con- 
ception that  the  life  processes  are  those  of  oxidation  with  the 
elimination  of  heat.  Technically,  the  problem  was  beset  with 
many  difficulties,  for  it  was  necessary  not  only  to  measure  the 
amount  of  heat  lost  by  radiation  and  conduction  from  the  body 
(direct  calorimetry),  but  also  to  collect  accurately  the  various 
end  products  resulting  from  combustion  within  the  body,  from 
which  data  the  heat  production  can  be  calculated  (indirect  calo- 
rimetry), in  order  to  prove  from  a  comparison  of  the  results 
obtained  from  the  two  methods  that  the  law  of  conservation  of 
energy  also  holds  for  the  living  organism.  Furthermore,  before 
the  method  of  indirect  calorimetry  could  be  employed  the  heat 
values  of  carbohydrate,  fat,  and  protein  had  also  to  be  deter- 
mined in  order  to  calculate  the  heat  derived  from  their  com- 
bustion in  the  body.  The  solution  of  these  problems  was  greatly 
advanced  by  Carl  Voit  (23)  and  his  pupils,  the  chief  of  whom 

71 


Reprinted  from  Rndocrinology,  1920, 
IV.  No.  1.  January-March.  71-87 


72         METABOLISM  IN  EXOPHTHALMIC  GOITRE 

were  Pettenkofer  (22)  and  Rubner  (27).  The  heat  values  of 
carbohydrate  and  fat  were  readily  determined  by  Rubner  (25) 
since  these  two  substances  are  oxidized  to  the  saine  end  products 
(carbon  dioxid  and  water)  whether  burning  in  the  body  or  in 
a  calorimeter.  In  the  case  of  protein,  however,  the  problem  was 
somewhat  more  difficult,  for  a  part  of  the  end  products  of  pro- 
tein combustion  in  the  body  is  eliminated  in  the  urine  and  feces 
and  the  latent  heat  thereby  lost  had  to  be  subtracted  from  the 
heat  value  of  protein  as  determined  in  the  calorimeter. 

In  1894  Rubner  (26)  constructed  the  first  successful  respi- 
ration calorimeter  designed  for  the  measurement  of  the  gaseous 
exchange  between  a  living  organism  and  the  atmosphere  which 
surrounds  it  and  the  simultaneous  measurement  of  the  quantity 
of  heat  produced  by  that  organism.  By  means  of  this  apparatus 
Rubner  verified  the  method  of  Pettenkofer  and  Voit  of  calcu- 
lating the  heat  production  (indirect  calorimetry)  and  he  proved 
that  the  law  of  conservation  of  energy  holds  for  the  living  or- 
ganism. 

It  was  not  until  1905  that  the  respiration  calorimeter  was 
brought  to  a  high  degree  of  technical  perfection  by  Atwater 
and  Benedict  (1).  "With  their  apparatus  it  was  possible  to 
determine  simultaneously  with  the  measurement  of  the  heat 
elimination,  not  only  the  carbon  dioxid  production,  but  also  the 
oxygen  consumption  of  the  subject.  Studies  made  by  Benedict 
and  his  associates,  at  the  Carnegie  Nutrition  Laboratory,  using 
the  perfected  calorimeter,  have  added  greatly  to  the  exactness 
of  our  knowledge  with  regard  to  the  metabolism  in  prolonged 
fasting  (4),  the  metabolism  of  normal  persons  (6),  of  infants 
(8),  and  of  diabetics  (7).  They  also  confirmed  the  agreement 
between  direct  and  indirect  calorimetry.  Lusk  (18)  and  Du  Bois 
and  their  co-workers  have  likewise  demonstrated,  in  a  large 
series  of  pathologic  conditions,  the  close  agreement  between  the 
two  methods.  As  a  result  of  these  investigations  the  use  of  such 
a  complicated  apparatus  as  the  respiration  calorimeter  has  been 
shown  to  be  unnecessary  for  clinical  work  and  that  in  its  place 
the  comparatively  simple  method  of  indirect  calorimetry  may 
be  used. 

Krogh  (16)  of  Copenhagen,  and  Carpenter  (11)  of  the 
Carnegie  Nutrition  Laboratory,  have  described  and  compared  in 


SANDIFORD  73 

great  detail  the  various  kinds  of  respiration  apparatus  used  in 
indirect  ealorimetry.  Carpenter  has  shown  that  for  indirect  de- 
terminations two  types  of  apparatus  are  suitable,  the  closed  cir- 
cuit and  the  gasometer. 

By  far  the  best  apparatus  of  the  closed  circuit  type  is  the 
Benedict  unit  apparatus  (2).  By  means  of  a  mask,  mouthpiece 
or  nasal  tubes,  the  subject  rebreathes  air  from  a  closed  system 
in  which  the  carbon  dioxid  is  absorbed  by  soda  lime,  and,  as 
the  oxygen  is  used  up,  it  is  replaced  by  oxygen  in  known  amounts. 
The  air  within  the  apparatus  is  kept  in  constant  circulation  by 
means  of  a  blower.  A  small  spirometer  is  inserted  in  the  cir- 
cuit as  an  expansion  chamber  and  volumetrically  records  the  re- 
spiratory movements  on  a  smoked  drum.  Knowing  the  weights 
of  oxygen  used  and  the  carbon  dioxid  eliminated,  one  can  readily 
calculate  the  heat  production.  As  pointed  out  by  Carpenter, 
this  apparatus  is  very  satisfactory  and  indeed  the  best  for  many 
purposes,  especially  when  used  in  conjunction  with  a  calori- 
meter or  with  the  cot-chamber  calorimeter  described  by  Bene- 
dict and  Tompkins  (9).  "We  have  found,  however,  that  for 
clinical  work  the  unit  apparatus  is  rather  cumbersome.  It  re- 
quires constant  checking  to  see  that  it  is  absolutely  air  tight, 
for  a  leak  of  20  or  30  c.c.  during  a  fifteen  minute  determination 
will  appreciably  affect  the  result,  because  such  a  leak  in  this 
type  of  apparatus  will  be  equivalent  to  the  loss  of  so  much  oxy- 
gen and  not  equivalent  to  the  loss  of  so  much  air  as  is  the  case 
in  the  gasometer  method.  Furthermore,  the  accumulation  errors 
of  the  apparatus  fall  on  the  oxygen  and  not  on  the  carbon 
dioxid  determination,  thus  causing  an  error  in  the  calculation  of 
the  respiratory  quotient  and  heat  production.  The  absorbing 
chemicals  must  be  changed  frequently  and  with  the  repairing 
and  constant  checking  of  the  apparatus  it  is  on  the  whole  difficult 
to  use  in  clinical  work,  particularly  if  many  determinations  are 
to  be  made. 

The  portable  respiration  apparatus  recently  devised  by 
Benedict  (5)  for  clinical  work  is  a  modification  of  liis  unit  ap- 
paratus described  above.  It  is  designed  primarily  to  give  a  rapid 
and  at  the  same  time  a  comparatively  accurate  measurement  of 
the  oxygen  consumption  without  involving  analyses  or  weighing. 
We  have  not  adopted  it,  as  we  prefer  to  determine  not  only  the 


74         METABOLISM  IN  EXOPHTHALMIC  GOITRE 

oxygen  consumption,  but  also  the  carbon  dioxid  elimination 
since  the  heat  production  can  thereby  be  more  accurately  cal- 
culated. Moreover,  the  diflEiculties  inherent  in  the  closed  circuit 
type  of  apparatus  are  still  present  in  the  portable  apparatus. 

For  clinical  work  the  gasometer  method  introduced  by 
Tissot  (29)  in  1904  is  considered  by  us  the  most  satisfactory. 
Briefly,  the  determinations  are  made  in  the  following  manner: 
A  mask  is  adjusted  over  the  patient's  mouth  and  nose  and  by 
means  of  expiratory  and  inspiratory  valves  the  total  volume  of 
the  patient's  expired  air  is  collected  in  a  gasometer  for  a  known 
period  of  approximately  ten  minutes.  Duplicate  determinations 
are  made  of  the  carbon  dioxid  and  oxygen  content  of  the  ex- 
pired air,  the  analyses  being  done  in  the  Haldane  gas  analysis 
apparatus  (14).  Since  the  ventilation  rate  for  each  minute  is 
known,  as  well  as  the  amount  of  carbon  dioxid  produced  and  the 
oxygen  absorbed,  it  is  possible  to  calculate  by  means  of  calorie 
tables  the  total  number  of  calories  produced  each  hour. 

The  following  points  in  the  routine  determination  of  the 
basal  metabolic  rate  deserve  further  discussion :  To  obtain 
comparable  results  the  patient  must  be  in  the  postabsorptive 
condition,  that  is,  he  must  fast  for  at  least  twelve  hours  pre- 
ceding the  test.  It  is  very  important  that  this  rule  should  be 
observed,  because  all  kinds  of  foods  cause  an  increase  in  the  heat 
production  and  this  effect  may  not  entirely  disappear  for  twelve 
hours  after  their  ingestion  (28).  Moreover,  the  patient  must  be 
at  complete  rest  and  the  effects  of  previous  muscular  exertion 
eliminated  by  requiring  him  to  rest  in  bed  for  twenty  minutes 
before  the  test  is  started,  for  we  have  shown  in  a  series 
of  experiments  that  a  rest  period  of  this  length  of  time  is  quite 
sufficient  to  obtain  the  basal  metabolism  (10).  During  the  pre- 
liminary rest  period  an  observer  sits  with  the  patient,  noting 
at  intervals  the  character  and  rate  of  the  heart  beat  and  the 
respiration;  likewise,  about  the  middle  of  the  period,  the  blood 
pressures,  both  systolic  and  diastolic,  are  obtained.  After 
twenty  minutes '  rest  a  mask  is  accurately  adjusted  over  the  nose 
and  mouth  of  the  patient  and  securely  held  in  place  by  means 
of  tapes  so  that  there  is  no  leakage  of  air  around  the  mask 
(Fig.  1).  A  mask  is  preferable  to  either  a  mouthpiece  or  nasal 
tubes.     With  a  little  experience  it  is  possible  to  adjust  the  mask 


SANDIFORD 


75 


so  that  it  is  not  only  comfortable  for  the  patient,  but  also  air- 
tight. One  of  the  chief  advantages  of  the  gasometer  method  is 
that  should  a  very  slight  leak  of  a  few  cubic  centimeters  occur 
around  the  mask  during  the  course  of  an  experiment  the  end 


Fig.  1.     Mask  and  connections  showing  valves,  intake 
pipe  and  towel  with  tapes. 

result  is  not  appreciably  affected,  while  a  leak  of  a  similar  volume 
in  the  closed  circuit  apparatus  has  a  value  at  least  five  times  as 
great,  because  in  the  latter  case  it  is  equivalent  to  the  loss  or 
gain  of  so  much  pure  oxygen. 


76         METABOLISM  IN  EXOPHTHALMIC  GOITRE 

During  the  test  proper  the  observer  sits  with  the  patient, 
recording  his  pulse  and  respiration  rates  and  noting  and  record- 
ing on  a  special  chart  any  movements.  Care  is  taken  to  impress 
on  the  patients  that  even  slight  movements  materially  affect  the 


Fig.  2.    Moveable  gasometer, 

test  and  it  is  almost  always  possible  to  obtain  their  complete 
co-operation.  Sometimes,  however,  in  an  extremely  nervous 
person,  a  basal  rate  cannot  be  obtained  on  the  first  test.  Instead 
of  repeating  the  determination  the  same  day  the  patient  is  in- 


SANDIFORD  77 

structed  to  return  the  following  morning  for  a  second  test.  In 
such  instances  the  rate  will  occasionally  be  ten  points  lower 
than  that  obtained  the  first  time  when  the  patient  was  unduly 
nervous  and  frightened  about  an  unknown  procedure. 

The  total  volume  of  the  expired  air  is  collected  in  a  gaso- 
meter (Fig.  2)  over  a  known  length  of  time.  Unlike  in  the  work 
with  the  closed  circuit  apparatus  no  appreciable  error  is  intro- 
ducd  by  failing  either  to  start  or  stop  the  experimental  period  at 
exactly  the  end  of  a  normal  respiration,  a  difficult  thing  to  do 
with  accuracy  in  the  case  of  patients  who  breathe  irregularly. 
Samples  of  the  expired  air  are  then  collected  over  mercury  in 
sampling  tubes  and  analj^zed  in  duplicate  for  carbon  dioxid  and 
oxygen.  Approximately  10  c.c.  of  expired  air  are  transferred 
into  the  burette  of  the  Haldane  gas  analysis  apparatus  (Fig.  3) 
and  after  adjusting  certain  levels  the  reading  of  the  initial 
volume  of  the  sample  is  made,  reading  to  the  nearest  0.001  c.c. 
The  gas  sample  is  then  passed  back  and  forth  over  a  solution  of 
dilute  potash  to  absorb  the  carbon  dioxid.  The  levels  of  the  solu- 
tion are  again  adjusted  and  a  second  reading  of  the  volume  of  the 
remaining  gas  in  the  burette  made.  The  contraction  in  volume  of 
the  gas,  due  to  the  absorption  of  the  carbon  dioxid  by  the  potash 
solution,  divided  by  the  original  volume,  gives  the  percentage 
of  carbon  dioxid  in  the  expired  air.  In  like  manner  the  per- 
centage of  oxygen  is  determined,  potassium  pyrogallate  solu- 
tion being  used  as  the  absorbent  for  oxygen. 

The  gasometer  method  is  particularly  suitable  for  clinical 
work  because  each  step  in  the  procedure  can  be  checked  by  a 
second  as.sistant,  reducing  to  a  minimum  the  chance  of  technical 
errors.  Although  the  method  requires  care  and  accuracy  in 
every  part  of  the  procedure,  it  is  possible  to  teach  the 
technic  to  laboratory  workers  who  have  had  no  preliminary 
scientific  training  other  than  that  obtained  in  a  high  school. 
The  most  difficult  stop  in  the  procedure  is  the  analysis  of  the 
expired  air.  This,  liowever,  we  have  found  to  be  inconsider- 
able. Our  assistants  can  obtain  routinely  duplicate  analyses 
agreeing  within  0.04  per  cent  for  carbon  dioxid  and  0.06  per 
cent  for  oxygon,  and  thoy  are  able  also  to  take  entire  care  of 
thoir  gas  analysis  apparatus.  The  equipment  necessary  for  this 
rnotliod  is  sirii[)l('  and  inexpensive  and  when  properly  constructed 


78         METABOLISM  IN  EXOPHTHALMIC  GOITRE 

is  rarely  out  of  order  and,  except  for  cleaning,  requires  very- 
little  mechanical  care.  Furthermore,  the  apparatus  is  free  from 
the  many  mechanical  difficulties  inevitably  inherent  in  a  closed 
circuit  system  in  which  the  air  current  is  driven  by  an  electric 


Fig.  3.    Haldane  gas  analysis  apparatus. 

pump.  In  the  metabolism  laboratory  at  the  Mayo  Clinic  we  are 
averaging  30  cases  a  day  and  have  developed  a  very  definite  and 
routine  procedure  which  has  decreased  the  chance  of  technical 
error  to  less  than  1  per  cent.* 

*  The  details  of  the  technic  are  described  in  a  laboratory  man- 
ual by  Boothby  and  Sandiford  (10).  The  apparatus  may  be  obtained 
from  H.  N.  Elmer,  1136  Monadnock  Bldg.,  Chicago. 


SANDIFORD  79 

The  calculation  of  the  basal  metabolic  rate  from  the  experi- 
mental data  is  \ery  simple.  Knowing  the  volume  of  air  expired 
by  the  patient  in  a  minute  (the  ventilation  rate)  and  the  per- 
centage of  carbon  dioxid  and  oxygen  in  the  expired  air,  it  is 
possible  to  calculate  the  volume  of  oxygen  absorbed  by  the  pa- 
tient in  one  hour,  as  well  as  the  corresponding  amount  of  carbon 
dioxid  produced.  Since  the  respiratory  quotient,  that  is  the 
ratio  between  the  volume  of  carbon  dioxid  produced  and  the 
volume  of  oxygen  absorbed,  indicates  the  kind  of  food  being 
burned  at  the  time  of  the  determination,  and  since  by  means  of 
calorie  tables  the  calorific  value  of  one  liter  of  oxygen  absorbed 
by  the  body  in  the  burning  of  these  substances  is  known,  the 
total  heat  production  each  hour  can  be  calculated  readily.  The 
total  number  of  calories  must  be  divided  by  the  surface  area,  a 
factor  dependent  on  the  patient's  height  and  weight.  The  num- 
ber of  calories  for  each  square  meter  of  body  surface  each  hour 
must  then  be  compared  with  the  normal  standards  of  compari- 
son which  are  dependent  on  the  age  and  sex  of  the  patient.  For 
convenience,  basal  metabolic  rates  are  expressed  in  percentages 
of  the  normal,  and  when  the  heat  production  is  greater  than  the 
normal  the  percentage  is  plus,  and  when  less  than  normal  the 
percentage  is  minus. 

A  very  important  contribution  was  made  by  Du  Bois  (12, 
13)  in  determining  the  heat  production  in  normal  controls. 
Rubner  (24)  had  suggested  that  the  heat  production  of  an  indi- 
vidual is  proportional  to  his  surface  area.  For  the  determina- 
tion of  the  surface  area  Meeh  (21)  proposed  the  formula: 
Surface  area  in  square  centimeters^l2.3  (a  constant)  X 
weight  in  grams^^^.  However,  using  the  surface  area  ob- 
tained by  this  formula  as  a  basis  of  comparison,  the  heat  pro- 
duction of  normal  controls  still  showed  quite  wide  variations, 
although  not  so  great  as  wlien  compared  on  the  basis  of  weight 
alone.  By  exact  measurements  of  the  surface  area  of  several 
bodies  Du  Bois  demonstrated  an  error  in  the  above  formula  due 
in  greater  part  to  the  fact  that  the  height  of  the  subject  was 
neglected.  As  a  result  of  further  studies  Eugene  F.  Du  Bois  and 
Delafield  Du  Bois  (12,  13)  devised  a  formula  based  on  height 


80         METABOLISM  IN  EXOPHTHALMIC  GOITRE 

and  weight  by  means  of  which  the  surface  area  can  be  calculated 
with  an  average  error  of  1.7  per  cent.    This  formula  is : 

0.425  0.725 

A=W  X  H  X  71.84 

Where  A  is  the  surface  area  in  square  centimeters,  "W  is  the 
weight  in  kilograms  and  H  is  the  height  in  centimeters,  and 
71.84  is  a  constant.  On  the  basis  of  this  formula  they  then  con- 
structed a  height-weight  chart  by  means  of  which  the  surface 
area  can  be  estimated  at  a  glance.  Du  Bois  (12,  13),  using  this 
new  height-weight  chart  for  the  determination  of  the  surface 
area  in  conjunction  with  his  standards  of  normal  basal  metabo- 
lism with  regard  to  age  and  sex,  further  showed  that  the  metab- 
olism of  normal  persons  can  be  predicted  with  an  accuracy  of 
±10  per  cent.  This  fact  has  been  confirmed  both  by  Means  (20) 
and  by  Boothby  (19).  Benedict  (3)  has  severely  criticized  the 
method  of  predicting  the  heat  production  from  the  unit  of  sur- 
face area,  maintaining  "that  the  metabolism  or  heat  output  of 
the  human  body,  even  at  rest  does  not  depend  on  Newton's  law 
of  cooling,  and  therefore,  is  not  proportional  to  the  body  sur- 
face." Harris  and  Benedict  (15)  in  a  very  exhaustive  treatise 
have  reconsidered  the  entire  problem  of  the  prediction  of  the 
normal  basal  metabolic  rate  and  show  that  by  proper  biometric 
formulas  based  on  stature,  body  weight,  and  age  (the  same  fac- 
tors used  by  Du  Bois),  "results  as  good  as  or  better  than  those 
obtainable  from  the  constant  of  basal  metabolism  per  square 
meter  of  body  surface  can  be  obtained  by  biometric  formulas 
involving  no  assumption  concerning  the  derivation  of  surface 
area,  but  based  on  direct  physical  measurements."  Since  their 
publication  there  has  not  been  sufficient  time  to  study  in  detail 
the  fundamental  accuracy  of  the  two  methods  of  prediction ;  we 
have,  however,  tabulated  404  determinations  of  the  basal  meta- 
bolic rate  expressed  in  •  percentages  above  and  below  normal, 
using  both  the  standards  of  Du  Bois  and  of  Harris  and  Benedict. 
The  average  rates  of  all  the  cases  show  that  the  rates  obtained 
by  Harris  and  Benedict's  method  are  6.5  points  higher  than 
those  obtained  by  Du  Bois'  method.  The  parallelism  between 
the  results  obtained  by  the  two  methods  is  strikingly  shown  by 
the  fact  that  195  of  the  404  determinations  are  within  ±  2.5  of 
the  average  variation.     Only  52  of  the  entire  404  rates  deviate 


SANDIFORD  81 

more  than  7.5  from  the  average  variation.  The  comparative 
agreement,  therefore,  of  the  two  methods  is  very  satisfactory, 
indicating  as  it  does  the  similarity  of  both  methods  of  compari- 
son, and  supporting  in  a  high  percentage  of  the  cases  the  clini- 
cal conclusions  based  on  the  Du  Bois  and  Du  Bois  height-weight 
chart  and  the  Du  Bois  normal  standards  for  comparison. 

The  metabolism  laboratory  at  the  Mayo  Clinic  was  opened, 
in  March,  1917  by  Boothby  and  Sandiford,  under  the  clinical 
direction  of  Dr.  H.  S.  Plummer,  and  in  that  year  1143  metabolic 
rates  were  determined  on  549  patients.  At  that  time  the  number 
of  cases  that  could  be  studied  in  the  laboratory  in  proportion 
to  the  number  of  thyroid  cases  at  the  clinic  was  rela- 
tively small.  In  consequence,  considerable  care  was  taken  by 
Dr.  Plummer  to  select  typical  cases  of  the  various  groups  of 
thyroid  disorders  and  with  his  permission  this  analysis  of  the 
metabolic  rates  in  the  exophthalmic  goitre  cases  studied  during 
1917  is  presented. 

The  basal  metabolic  rate  is  of  the  greatest  value  in  thyroid 
disorders  because  it  gives  a  very  accurate  mathematical  index 
of  the  degree  of  functional  activity  of  the  thyroid  gland. 
For  example,  in  exophthalmic  goitre  the  metabolic  rate  may 
rise  "well  over  100  per  cent  above  normal  while  in  myxedema, 
with  apparently  complete  cessation  of  thyroid  activity,  the 
rate  falls  to  the  region  of  40  per  cent  below  normal.  In  the 
milder  cases  of  both  groups  the  metabolic  rate  variations 
from  the  normal  are  proportionately  smaller.  On  the  other 
hand,  beside  thyroid  disorders,  there  are  no  diseases  that 
have  so  far  been  shown  to  have  a  constant  and  distinct  vari- 
ation from  the  normal  in  the  basal  metabolic  rate  except  disor- 
ders of  the  pituitary  gland,  conditions  of  profound  inanition, 
and  fevers.  However,  an  occasional  case  is  met  with  in  which 
there  is  a  variation  in  the  basal  metabolic  rate  that  at  present 
cannot  be  explained  or  properly  classified.  Such  variations 
are  more  frequent  in  patients  with  considerable  evidence  of 
nephritis  or  anemia.  No  definite  instance  of  an  increased 
basal  metabolic  rate  has  been  found  in  that  group  of  cases 
known  as  neurasthenia  or  chronic  nervous  exhaustion.  The 
basal  metabolic  rate  has  proved,  therefore,  to  be  of  great  value 


82         METABOLISM  IN  EXOPHTHALMIC  GOITRE 

in  the  differential  diagnosis  of  neurosis  simulating  hyper- 
thyroidism and  true  hyperthyroidism. 

In  182  cases  of  exophthalmic  goitre  before  any  treatment 
was  instituted  the  average  metabolic  rate  was  -|-51  per  cent, 
with  an  average  pulse  rate  of  115.  In  13  patients  whose  average 
metabolic  rate,  as  outpatients,  was  -\-o9  per  cent,  with  an  aver- 
age pulse  rate  of  115,  the  average  metabolic  rate  fell  to  -|-46 
per  cent,  and  the  average  pulse  rate  to  108  as  a  result  of  approxi- 
mately one  week's  complete  rest  in  bed.  In  5  patients  whose 
average  metabolic  rate,  determined  within  two  to  five  days  after 
they  entered  the  hospital,  was  -|-59  per  cent  and  the  pulse  118, 
after  a  further  rest  in  bed  of  approximately  one  week's  dura- 
tion there  was  a  definite  improvement  in  their  condition,  as 
shown  by  a  fall  in  the  metabolic  rate  to  an  average  of  -1-48  per 
cent  and  pulse  to  104» 

The  effect  of  a  single  ligation  was  studied  in  16  cases.  The 
basal  metabolic  rate  taken  after  the  patient  had  had  several 
days'  rest  in  bed  and  within  five  days  before  the  first  ligation 
was  -|-54  per  cent  and  the  pulse  116.  One  week  after  the  single 
ligation  the  average  metabolic  rate  had  decreased  to  -|-44  per 
cent  and  the  pulse  to  112. 

The  immediate  result  of  ligation  or  thyroidectomy  in  hyper- 
thyroidism is  to  cause  at  first  a  rise  in  the  metabolic  rate  for  a 
few  days,  followed  by  a  gradual  fall  to  a  distinctly  lower  level  on 
the  average  than  that  obtained  preceding  the  operation.  The 
curve  of  the  basal  metabolic  rate  on  the  average  roughly  par- 
allels the  pulse  rate  curve.  The  former  is,  however,  a  far  more 
accurate  index  of  the  degree  of  hyperthyroidism  than  is  the 
pulse  rate,  as  the  latter  shows  more  individual  and  extraneous 
variations,  for  example,  the  irregularities  of  auricular  fibril- 
lation. 

The  effect  of  the  second  ligation  is  likewise  a  general 
improvement  in  the  patient's  condition  as  evidenced  by  a 
decrease  in  the  metabolic  rate.  An  average  figure  of  any 
value  on  the  immediate  result  of  the  second  ligation  in  the  pa- 
tients in  the  1917  series  cannot  be  given,  as  practically  no  rates 
were  obtained  in  the  same  case  immediately  preceding  and  fol- 
lowing the  second  ligation.  There  is  a  very  marked  improve- 
ment in  these  patients  when  they  return  for  their  thyroidectomy 


SANDIFORD  83 

two  to  four  months  after  the  second  ligation.  In  22  patients 
(Table  1)  there  was  an  average  decrease  in  the  basal  metabolic 
rate  from  -(-46  per  cent  to  -|-  39  per  cent,  and  in  the  pulse  from 
115  to  107  with  a  gain  in  weight  from  46.4  to  54.5  kilograms  in 
the  determinations  made  a  few  days  after  the  second  ligation  as 
compared  with  the  data  obtained  after  three  months'  rest  at 
home  and  just  previous  to  thyroidectomy.  From  the  clinical 
history  it  is  probable  that  the  basal  metabolic  rate  determined 
at  the  time  the  patients  returned  for  operation  after  having 
had  two  ligations  and  three  months'  rest  at  home  may  not 
necessarily  represent  in  all  cases  the  period  of  maximum  im- 
provement produced  by  the  two  ligations  and  rest.  A  definite 
improvement  from  thyroidectomy  in  those  patients  who  had  had 
two  ligations  and  a  three  months'  rest  was  shown  two  weeks  fol- 
lowing operation  by  a  decrease  in  the  basal  metabolic  rate  from 
-|-39  per  cent  to  -\-16  per  cent,  and  in  the  pulse  rate  from  107 
to  89. 

In  another  group  of  19  patients  (Table  2)  with  exophthal- 
mic goitre  in  whom  the  preliminary  basal  metabolic  rate  varied 
between  +13  per  cent  and  +50  per  cent,  giving  an  average  of 
+31  per  cent  with  an  average  pulse  rate  of  104,  and  in  whom 
a,  primary  thyroidectomy  was  done  without  any  other  prelimin- 
ary treatment,  except  for  a  short  rest  in  bed,  the  basal  metabolic 
rate  fell,  about  two  weeks  after  operation,  to  +5  per  cent  and 
the  pulse  to  84. 

The  general  effect  of  the  treatment  adopted  at  the  Mayo 
Clinic  for  severe  cases  of  exophthalmic  goitre  may  be  illustrated, 
then,  by  the  following  data:  In  a  group  of  22  patients  (Table 
1)  the  average  basal  metabolic  rate,  before  any  treatment  was 
instituted,  was  +66  per  cent,  with  a  pulse  rate  of  123.  As  a 
result  of  rest  in  bed  and  two  ligations  the  rate  in  these  patients 
before  they  went  home  had  decreased  to  +46  per  cent  and  the 
pulse  to  115.  The  further  improvement  that  occurred  from 
three  months'  rest  at  home  reduced  the  average  metabolic  rate 
to  +39  per  cent  and  the  pulse  rate  to  107  and  finally,  after 
thyroidectomy  and  just  before  the  patients  were  discharged  from 

As  will  be  noted,  following  thyroidectomy  there  is  almost 
always  a  marked  decrease  in  the  basal  metabolic  rate  within 
the  clinic,  the  rate  was  +16  per  cent  and  the  pulse  89. 


84        METABOLISM  IN  EXOPHTHALMIC  GOITRE 


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SANDIFOED  85 

two  weeks  after  the  operation  and,  as  a  rule,  there  is  still  fur- 
ther improvement  in  the  succeeding  months,  just  as  is  seen  to 
occur  in  the  interval  after  the  second  ligation.  Occasionally,  a 
varying  degree  of  hyperthyroidism  may  persist,  as  shown  by 

Table  2 

THE   EFFECT   OF   PRIMARY   THYROIDECTOMY   ON   THE 
BASAL  METABOLIC  RATE  IN  EXOPHTHALMIC  GOITRE 


About  two  weeks 

Before  treatment 

after 

operation 

Case 

Pulse 

B.  M.  R. 
Per  cent 

Pulse 

B.  M.  R, 
Per  cent 

214581 

88 

+50 

70 

+19 

196806 

109 

+45 

93 

+  3 

202992 

107 

+45 

92 

+  5 

200219 

145 

+42 

115 

+12 

201229 

102 

+40 

75 

+14 

202481 

105 

+39 

68 

+  1 

202527 

112 

+36 

92 

+15 

194686 

97 

+35 

75 

+  1 

212298 

108 

+34 

91 

+  5 

202232 

113 

+32 

118 

+32 

203326 

127 

+30 

89 

+10 

3396 

101 

+29 

83 

+13 

198725 

99 

+27 

67 

0 

196664 

79 

+21 

58 

—11 

203291 

87 

+18 

73 

—  6 

199740 

95 

+18 

69 

—  7 

217150 

99 

+16 

85 

—  5 

215895 

118 

+16 

98 

—  9 

208637 

89 

+13 

84 

+  6 

Average  104  +31  84  +5 

an  elevated  basal  metabolic  rate.    In  these  cases  a  second  (and 
rarely  a  third)  thyroidectomy  is  indicated. 

BIBLIOGRAPHY 

1.  Atwater,  W.  O.,  and  Benedict,  F.  G. :     A  respiration  calorimeter 

with  appliances  for  the  direct  determination  of  oxygen.     Car- 
negie Inst.,  Washington,  1905,  Pub.  No.  42, 

2.  Benedict,    F.   G. :      Ein   Universalrespirationsapparat.      Deutsch. 

Arch.  f.  klin.  Med.,  1912,  107,  156. 

3.  Benedict,  F.  G. :     Factors  affecting  basal  metabolism.    Jour.  Biol. 

Chem.,  1915,  20,  263-313. 

4.  Benedict,  F.  G. :     A  study  of  prolonged  fasting.     Carnegie  Inst., 

Washington,  1915,  Pub.  No.  203. 


86         METABOLISM  IN  EXOPHTHALMIC  GOITRE 

5.  Benedict,  F.  G. :     A  portable  respiration  apparatus  for  clinical 

use.     Boston  Med.  and  Surg.  Jour.,  1918,  178,  567. 

6.  Benedict,  F.  G.  and  Carpenter,  T.  M.:     Metabolism  and  energy 

transformation  of  healthy  man  during  rest.     Carnegie  Inst., 
Washington,  1910,  Pub.  No.  126. 

7.  Benedict,  F.  G.,  and  Joslin,  E.  L.:     Metabolism  in  diabetes  mel- 

litus.     Carnegie  Inst.,  Washington,  1910,  Pub.  No.  136. 
A  study  of  metabolism  in  severe  diabetes.    Carnegie  Inst.,  Wash- 
ington, 1912,  Pub.  No.  176. 

8.  Benedict,  F.  G.,  and  Talbot,  F.  B. :     The  gaseous  metabolism  of 

infants.     Carnegie  Inst.,  Washington,  1914,  Pub.  No.  201. 
The  physiology  of  the  new-born  infant.     Carnegie  Inst.,  Wash- 
ington, 1914,  Pub.  No.  233. 

9.  Benedict,    F.    G.,    and    Tompkins,   Edna   H,:      Respiratory   ex- 

change, with  a  description  of  a  respiration  apparatus  for  clin- 
ical use.     Boston  Med.  and  Surg.  Jour.,  1916,  174,  857. 

10.  Boothby,  W.  M.,  and  Sandiford,  Irene:     Technic  of  basal  meta- 

bolic rates  determinations.     Philadelphia,  Saunders,  1920. 

11.  Carpenter,  T.  M. :     A  comparison  of  methods  for   determining 

the  respiratory  exchange  of  man.    Carnegie  Inst.,  Washington, 
1915,  Pub.  No.  216. 

12.  Du  Bois,  D.,  and  Du  Bois,  E.  F. :     The  measurement  of  the  sur- 

face  area   of  man.      Clinical   calorimetry.      Paper   V.     Arch. 
Int.  Med.,  1915,  15,  868-881. 

13.  Du  Bois,  D.,  and  Du  Bois,  E.  F. :     A  formula  to  estimate  the  ap- 

proximate surface  area  if  height  and  weight  be  known.     Clin- 
ical calorimetry,  Paper  X.  Arch.  Int.  Med.,  1916,  17,  863-871. 

14.  Haldane,  J.  S. :  Methods  of  air  analysis.    London,  Griffin,  1912. 

15.  Harris,  J.  A.,  and  Benedict,  F.  G. :     A  biometric  study  of  basal 

metabolism  in  man.     Carnegie   Inst.,  Washington,  1919,  Pub. 
No.  279. 

16.  Krogh,  A.:     The  respiratory  exchange  of  animals  and  man  (with 

excellent  bibliography) .    London,  Longmans,  Green  &  Co.,  1916. 

17.  Lavoisier,  A.  L.,  and  Laplace:     Memoire  sur  la  chaleur.     Mem. 

de  math,  et  de  phys.  de  FAcad.  d.  Sc,  1780,  355. 
Lavoisier,  A.  L.,  and  Seguin:     Premier  memoire  sur  la  respira- 
tion des  animaux.    Mem.  de  math,  et  de  phys.  de  lAcad.  d.  Sc, 
1789,  566.     (Also:     "Oeuvres  de  Lavoisier,"  1862). 

18.  Lusk,  G. :     A  series  of  papers  on  clinical  calorimetry  by  Lusk 

and  his  associates  appearing  in  Arch.  Int.  Med.,  beginning  in 
1915,  15. 

19.  Lusk,  G. :     Science  of  nutrition.     Philadelphia,  Saunders,  3  ed., 

1917,  641  pp. 

20.  Means,  J.  H. :     Basal  metabolism  and  body  surface.     A  contri- 

bution to  the  normal  data.  Jour.  Biol.  Chem.,  1915,  21,  263-268. 

21.  Meeh,   K. :     Oberflachenmessungen    des     menschlichen     Korpers. 

Ztschr.  f.  Biol.,  1879,  15,  425-458. 

22.  Pettenkoffer,   M. :      Ueber    die   Respiration.      Ann.   d.    Chem.   u. 

Pharm.,  1862,  2,  Suppl.  1. 
23'.     Pettenkoffer,  M.,  and  Voit,  C:     Untersuchungen  iiber  die  Respi- 
ration.    Ann.  d.  Chem.  u.  Pharm.,  1862,  Suppl.  52. 

24.  Rubner,  M.:     Ueber  den  Einfluss  der  Korpergrosse  auf  Stoff-und 

Kraftwechsel.     Ztschr.  f.  Biol.,  1883,  19,  535-562. 

25.  Rubner,  M.:     Calorimetrische  Untersuchungen.     Ztschr.  f.  Biol., 

1885,  21,  250-334. 


SANDIFORD  87 

26.  Rubner,  M. :    Die  Quelle  der  tierischen  Warme    (Comparison  of 

direct  and  indirect  calorimetry).     Ztschr.  f.  Biol.,  1894,  30,  73. 

27.  Rubner,  M. :     Die  Gesetze  des  Enerp^ieverbrauchs  bei  der  Ernah- 

rung.     Leipsic,  Deuticke,  1902,  426  pp. 

28.  Soderstrom,  G.  F.,  Barr,  D.  P.  and  Du  Bois,  E.  F.:     The  effect 

of  a  small  breakfast  on  heat  production.     Clinical  calorimetry, 
Paper  XXVI.     Arch.  Int.  Med.,  1918,  21,  613-620. 

29.  Tissot,  J.:     Nouvelle  methode   de  mesure    et    d'inscription    du 

debit  et  des  mouvements  respiratoires  de  I'homme  et  des  ani- 
maux.    Jour,  de  phys.  et  de  path,  gen.,  1904,  6,  688. 


END  O  C  R I N  O  L  O  G  Y 


EDITORIAL  STAFF 


Prof.  R.  G.  Hoskins,  Editor-in-Chief,  Baltimore 


Prof.  Isaac  A.  Abt Northwestern  University,  Chfcago 

Prof.  Lewellys  F.  Barker.  .Johns  Hopkins  University,  Baltimore 

Prof.  Walter  B.  Cannon Harvard  Medical  School,  Boston 

Prof.  Harvey  Cushinc Harvard  Medical  School,  Boston 

Prof.  E.  Gley University  of  Paris 

Prof.  B.  A.  Houssay University  of  Buenos  Aires 

Sir  Edward  Sharpey  Schafer .' . . .  University  of  Edinburgh 

Prof.  Swale  Vincen't. University  of  Manitoba,  Winnipeg 

Prof.  Frank. A.  Hartman Universitj'  of  Buffalo 

Dr.  E.  C.  Kendall Mayo  Clinic,  Rochester,  Minn. 

Dr.  W.  H.  Morley Pontiac,  Mich, 


COLLABORATORS 

Prof.  T.  C.  Eurkett University  of  California,  Berlteley 

Dr.  G.  p.  GofJALONS Buenos  Aires,  Argentine 

Dr.  Murray  B.  Gordon Brooklyn 

Dr.  Frederick  S.  Hammett Philadelphia 

Dr.  \Villia.\i  Harrison   (Bibliographer) Detroit 

Dr.  E.  K.  Hoskins* University  of  Minnesota,  Minneapolis 

Dr.  J.  KoopMAN The  Hague,  Holland 

Dr.  KsuD   H.    ICrabbe Copenhagen,   Denmark 

Dr.  Joshua  H.  Leiner New  York 

Dr.  H.  Lisser San  Francisco 

Dr.  Ketil  Motzfeldt Christiana,  Norway 

Dr.  Joel  Rodiquez  P University  of  Chile,  Santiago 

Prof.  Hector  Rosello Montevidio,  Uruguay 

Prof.  J.  P.  Simonds Northwestern  University  Medical  School,  Chicago 

Dr.  Burton  T.  Simpson BuSalo 

Prof.  Arthur  L.  Tatum University  of  Chicago 

Dr.  L.  F.  Watson Chicago 

Dr.  Homer  Wheelon St.  Louis 

Dr.  G.  Veecellini St  Paul 


\  Deceased. 


Reprinted  form  The  American  Journal  of  Physiologt, 
Vol.  51,  No.  3,  April,  1920 


THE  EFFECT  OF  THE  SUBCUTANEOUS  INJECTION  OF 

ADRENALIN  CHLORID  ON  THE  HEAT  PRODUCTION, 

BLOOD  PRESSURE  AND  PULSE  RATE  IN  MAN 

IRENE  SANDIFORD 
From  the  Mayo  Foundation,  University  of  Minnesota,  Rochester,  Minn. 

Received  for  publication  January  22,  1920 

The  results  of  previous  studies  of  the  ejffect  on  the  respiratory  ex- 
change of  the  injection  of  adrenahn  chlorid  may  be  briefly  summarized: 
An  increase  in  the  respiratory  quotient  was  found  by  Fuchs  and  Roth 
(1),  Hari  (2),  Bernstein  and  Falta  (3),  Lusk  and  Riche  (4),  (5)  and  by 
Tompkins,  Sturgis  and  Wearn  (6).  La  Franca  (7),  Wilenko  (8)  and 
Bernstein  (9)  found  no  change.  A  greater  oxygen  consumption  or  cal- 
orific output  than  normal  was  noted  by  La  Franca  (7),  Fuchs  and  Roth 
(1),  Bernstein  and  Falta  (3),  Bernstein  (9),  Lusk  and  Riche  (4),  (5), 
and  by  Tompkins,  Sturgis  and  Wearn  (6) ;  Wilenko  (8)  found  no  change 
in  the  oxygen  consumption  and  Hari  (2)  and  Jackson  (10)  found  a 
decrease. 

Of  these  contributions  the  most  important  is  that  of  Tompkins,  Stur- 
gis and  Wearn  (6).  In  a  carefully  controlled  series  of  34  experiments 
they  obtained,  without  exception,  an  increase  in  the  heat  production 
following  the  injection  of  adrenalin  chlorid  (0.5  cc.  of  1/1000)  and  this 
increase  was  usually  accompanied  by  a  rise  in  the  respiratory  quotient 
(27  experiments).  Soldiers  were  studied;  they  were  divided  into  three 
groups:  a,  Those  with  "irritable  heart;"  h,  those  with  hyperthyroidism; 
and  c,  normal  men,  that  is,  well-trained  active  soldiers  on  full  duty. 
There  were  25  soldiers  with  "irritable  heart,"  in  13  of  whom  the  in- 
crease in  the  metabolism  from  the  adrenalin  injection  was  accompanied 
by  an  increase  in  the  pulse  rate  and  systolic  blood  pressure  of  at  least 
ten  points  each,  while  in  12  there  was  a  less  marked  increase.     In  the  3 

407 

THE  AMERICAN  JOURNAL  OF  PHTSIOLOOY,  VOL.  51,  NO.  3 


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REACTIONS   TO   SUBCUTANEOUS   INJECTION    OF   ADRENALIN         413 

cases  of  hyperthyroidism  there  was  an  increase  of  more  than  ten  points 
in  both  the  pulse  and  systohc  blood  pressure,  while  in  the  6  normal  sol- 
diers on  active  duty  the  response  in  the  pulse  rate  and  systolic  blood 
pressure  was  less  definite. 

Before  the  pubhcation  of  the  paper  by  Tompkins,  Sturgis  and  Wearn, 
an  investigation  on  the  effect  of  the  subcutaneous  injection  of  adrenalin 
on  the  heat  production,  pulse  rate,  and  blood  pressure  had  been  started  in 
this  laboratory;  a  preliminary  report  has  recently  been  made  (11)  of  the 
results  given  here  in  detail.  The  method  of  procedure  was  as  follows: 
The  patients  came  to  the  laboratory  in  the  so-called  post-absorptive  con- 
dition and  the  basal  metaboUc  rate,  pulse  rate,  and  blood  pressure  were 
determined  after  the  patients  had  rested  in  bed  twenty  minutes  accord- 
ing to  the  regular  routine  practiced  in  this  laboratory  and  described 
m  detail  elsewhere  (12).  For  the  determination  of  the  basal  metabolic 
rate  a  mask  is  tightly  adjusted  over  the  patient's  mouth  and  nose  and, 
by  means  of  expiratory  and  inspiratory  valves,  the  total  volume  of  the 
patient's  expired  air  is  collected  in  a  gasometer  for  a  known  period  of 
approximately  ten  minutes.  Duphcate  determinations  are  made  of  the 
carbon  dioxid  and  oxygen  content  of  the  expired  air,  the  analyses  being 
done  in  the  Haldane  gas  analysis  apparatus.  From  the  data  obtained 
the  basal  metabolic  rate  is  calculated  by  the  usual  method. 

After  the  various  basal  values  have  been  determined,  0.5  cc.  of  l/lOOO 
solution  of  adrenalin  chlorid  (Parke,  Davis  &  Company)  is  injected 
subcutaneously  in  the  patient's  arm;  the  pulse  and  blood  pressure  are 
taken  every  five  minutes  for  the  next  two  hours  and  the  metabolic 
rate  determined  for  approximately  ten-minute  periods  beginning  about 
ten  minutes,  thirty  minutes,  one  hour,  and  one  and  one-half  hours  after 
the  injection. 

Forty-six  experiments  were  done  on  the  39  patients  grouped  accord- 
ing  to  diagnosis  in  table  1.  The  results  of  these  experiments  are  sum- 
marized in  table  2.  Four  experiments  in  group  1  are  not  included  in 
the  average  given  in  table  2  because  the  dose  of  adrenahn  was  less 
than  0.5  cc;  2  experiments  in  group  2,  1  in  group  3,  1  in  group  8,  2  in 
group  9  and  1  in  group  13  are  not  included  in  the  average  because  of 
previous  thyroxin  administration.  The  experiments  omitted  from  the 
average  are  starred  in  table  1.  The  data  obtained  as  basal  before  the 
adrenalin  injection  are  contrasted  in  table  1  with  the  data  which  showed 
the  most  pronounced  reaction  following  the  injection.  The  percentage 
increase  over  the  basal  is  given  for  the  total  calories,  pulse  rate,  and 
systolic  blood  pressure.     In  table  2  arc  given  the  average  data  for  the 


414 


lEENE    SANDIFORD 


various  groups  of  cases  studied.  In  table  3  are  grouped  those  cases  in 
which  the  adrenahn  test  was  done  both  before  and  after  the  patients 
were  given  thyroxin. 

TABLE  2 

Summary  of  the  effect  of  the  subcutaneous  injection  of  adrenalin  chlorid  on  the  sys- 
tolic blood  pressure,  pulse  rate,  respiration  rate,  ventilation  rate,  respiratory  quo- 
tient, total  calories  per  hour  and  basal  metabolic  rate  {standard  dose  of  adrenalin 
chlorid  0.5  cc.) 


6 
7 
8 
9 
10 
11 
12 
13 

14 


DIAGNOSIS 


Exophthalmic  goiters;  five  with  B. 

M.  R.  above  +50  per  cent 

Four  with  B.  M.  R.  below  +50  per 

cent 

Average  of  all  exophthalmic  goiters. . 
Adenomas  of  thyroid;  hyperthyroidism 
Double  oophorectomized  neurasthenic 

with  hyperthyroidism   

Adenoma  of  thyroid  without  hyper^ 

thyroidism 

Colloid  goiter;  hypothyroidism  .... 

Addison's  disease 

Hypopituitarism 

Myxedema 

Postoperative  myxedema 

Atypical  hypothyroidism  on  thyroxin. 
Anorexia  nervosa;  hypothyroidism  .. 
Neurasthenia   and    chronic   nervous 

exhaustion 

Normal  clinical  controls 


PERCENTAGE 
TABIATIONS 
FROM  BASAL 


per 
cent 


per 
cent 


+68 

+15 
+44 
+15 

+15 

+4 

-16 

-6 

-16 

-35 

-16 

+10 

-22 

+6 

+7 


per 
cent 


per 
cent 


NUMEKICAL  VARIA- 
TIONS FROM  BASAL 


..Q 

u    * 


2.82 

1.35 
2.17 

2.40 

5.38 

1.07 
1.51 
0.55 
1.84 
0.37 
1.74 
1.85 
0.59 

2.48 
1.72 


O  13 


0.12 

0.04 
0.08 
0.12 

0.11 

0.06 
-0.02 
-0.03 
0.16 
0.01 
0.10 
0.11 
0.01 

0.07 
0.03 


38 

17 

29 

27 

38 

11 
25 
15 

12 

7 

25 

45 

6 

24 
20 


DISCUSSION   OF   RESULTS 


Heat  'production.  In  every  experiment  there  was  an  increase  in  the 
heat  production  after  the  subcutaneous  injection  of  adrenahn  chlorid, 
the  maximum  occurring  as  a  rule  within  ten  to  thirty  minutes  after  the 


REACTIONS    TO    SUBCUTANEOUS    INJECTION    OF    ADRENALIN         415 

injection.  With  but  three  exceptions,  one  patient  with  severe  exoph- 
thahnic  goiter  in  whom  only  0.1  cc.  adrenahn  was  injected,  one  patient 
with  hypopituitarism,  and  one  patient  with  anorexia  nervosa,  this  maxi- 
mum increase  was  at  least  10  per  cent  above  the  basal;  the  greatest  reac- 
tion^was  48  per  cent  above  the  basal  and  occurred  in  a  case  of  chronic 
nervous  exhaustion.  Within  one  and  one-half  to  two  hours  after  the 
adrenahn  was  injected  the  metabolic  rate  had  returned  to  within  4 
points  of  the  preliminary  level  in  21  experiments;  it  was  still  somewhat 
elevated  in  19  experiments,  and  it  was  shghtly  lower  than  the  basal 


Tijpical  curve  of  tHe  perceT\.t)a,§e  irtcrease  i-u  the 
tota.1  calories  follvvjin^  fhe  ir\,^ection  o^  dd- 
rena-liTb     cKlorlcL'.    Dia^tvosis :   Ne-urastKeuxa  ■ 

Iw?^  Ca5eNo.A2.61£9a 

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40        60 
Fig.  1 


80       100       12.0 


determined  before  the  injection  in  the  remaining  6  experiments.  A 
typical  example  of  the  post-adrenaHn  metabohc  curve  is  given  in  figure  1. 
In  the  group  of  patients  with  exophthalmic  goiter  with  basal  metabolic 
rates  above  -|-50  per  cent  who  were  given  the  standard  dose  of  adre- 
nalin the  total  number  of  calories  per  hour  increased  on  the  average  22 
per  cent  over  the  basal,  while  in  the  group  of  patients  with  a  milder  de- 
gree of  exophthalmic  goiter  whose  basal  metabolic  rates  were  less  than 
-1-50  per  cent  the  total  number  of  calories  increased  on  the  average  15 
per  cent.     In  spite  of  this  no  consistent  relationship  can  be  seen  in  the 


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416 


REACTIONS    TO    SUBCUTANEOUS    INJECTION    OF   ADRENALIN         417 

various  groups  studied  and  summarized  in  table  2,  between  the  height 
of  the  adrenahn  reaction  and  the  degree  of  hyperthyroidism  or  hypo- 
thyroidism as  determined  by  the  level  of  the  metabolic  rate.  This  in- 
consistency is  further  shown  in  the  6  cases,  (table  3)  in  which  the  adre- 
nalin reaction  was  studied  both  before  and  after  the  intravenous  injec- 
tion of  thyroxin  for  in  two  of  these  the  percentage  increase  in  the  total 
calories  after  the  adrenalin  injection  was  less  instead  of  greater  in  the 
adrenahn  test  carried  out  after  the  patients  had  received  thyroxin. 
Furthermore,  there  is  only  a  very  slight  difference  in  the  average  in- 
crease in  the  heat  production  from  the  adrenalin  injection  before  thy- 
roxin was  administered  (17  per  cent)  as  compared  with  the  average 
increase  after  thyroxin  was  given  (21  per  cent). 

The  metabolic  curve  resulting  from  the  subcutaneous  injection  of 
adrenalin  is  entirely  different  from  that  found  by  Plummer  following 
the  intravenous  injection  of  16  mg.  of  thyroxin.  Following  the  injec- 
tion of  adrenalin  the  height  of  the  metabolic  curve  is  reached  in  approxi- 
mately from  ten  to  thirty  minutes  and  has  returned  to  its  basal  level  in 
about  two  hours;  when  thyroxin  is  injected,  however,  the  height  is  not 
reached  for  approximately  from  three  to  ten  days  and  the  basal  level 
not  regained  for  from  one  to  two  months.  The  presence  of  hypergly- 
cemia (13)  following  the  injection  of  adrenalin  chlorid  naturally  directs 
attention  to  the  similarity  of  the  post-adrenalin  metabolic  curve  to 
that  found  by  Lusk  (14)  as  a  result  of  carbohydrate  plethora  following 
the  ingestion  of  glucose. 

Ventilation  and  respiration  rates.  There  is  invariably  an  increase  in 
the  ventilation  rate  following  the  injection  of  adrenalin  chlorid  and  this 
is  usually  accompanied  by  an  increase  in  the  respiration  rate,  although 
there  may  even  be  a  decrease  in  the  latter.  The  variations  in  the 
percentages  of  carbon  dioxid  eliminated  in  the  expired  air  and  of  oxygen 
absorbed  from  the  inspired  air  vary  inversely  with  the  changes  in  the 
ventilation  rate  and  directly  with  the  increase  in  the  metabolism. 
It  is  impossible,  however,  to  predict  the  degree  with  which  the  increase 
in  the  respiratory  volume  will  predominate  over  the  concentration  of 
that  volume  in  different  individuals  or  even  in  the  same  individual  at 
different  times. 

Respiratory  quotient.  Following  the  injection  of  adrenalin  there  was 
an  increase  in  the  respiratory  quotient  in  39  experiments,  no  change  in 
1  experiment,  and  a  decrease  in  6.  These  results  taken  in  conjunction 
with  those  of  Tompkins,  Sturgis  and  Wearn  (0)  indicate  that  as  a  rule 
there  is  an  increase  in  carbohydrate  combustion;  this  is  confirmed  by 


418  IRENE   SANDIFORD 

the  jfindings  of  other  observers  of  an  increase  in  the  blood  sugar  (13) 
following  the  injection  of  adrenalin.  The  action  of  adrenalin,  there- 
fore, is  not  only  to  cause  a  higher  rate  of  oxidation  but  also  to  mobilize 
carbohydrate  as  fuel  for  this  increased  combustion;  which  reaction  is 
primary  is  not  known. 

Diastolic  blood  pressure.  Throughout  the  groups  there  is  no  constant 
variation  in  the  diastolic  blood  pressure.  In  19  experiments  there  was 
an  increase,  in  7  there  was  no  change,  and  in  20  there  was  a  decrease. 
If  the  peripheral  capillary  cross  section  remains  constant  when  the 
blood  flow  is  increased  the  diastoHc  blood  pressure  necessarily  rises; 
an  unchanged  or  decreased  diastolic  with  increased  blood  flow  would 
indicate  a  compensatory  peripheral  dilatation.  Even  a  certain  propor- 
tion of  those  experiments  that  showed  a  slight  increase  in  diastolic 
blood  pressure  may  likewise  have  had  a  slight  peripheral  dilatation 
that  was  not,  however,  of  sufficient  degree  entirely  to  compensate  for 
the  increased  blood  flow.  A  peripheral  compensatory  dilatation  is, 
therefore,  indicated  by  the  data  in  27  experiments;  it  may  have  occurred 
in  an  unknown  proportion  of  the  other  19  experiments.  Further  evi- 
dence of  peripheral  dilatation  is  shown  by  the  flushing  of  the  skin 
and  increased  perspiration,  which  are  ph"ysical  compensatory  factors 
to  accommodate  the  body  to  the  increased  production  of  heat. 

Systolic  blood  pressure.  An  increase  in  the  systolic  blood  pressure 
was  noted  in  all  but  4  cases  following  the  adrenalin  injection.  These 
four  are  as  follows:  One  case  of  adenomas  of  the  thyroid  without 
hyperthyroidism  with  a  basal  metabohc  rate  of  +4  per  cent;  one  case 
of  hypopituitarism  with  a  basal  metabolic  rate  of  —28  per  cent;  one 
case  of  post-operative  myxedema  with  a  basal  metabolic  rate  of  —13 
per  cent;  and  one  case  of  neurasthenia  with  a  rate  of  +28  per  cent 
after  an  injection  of  thyroxin.  In  18  cases  the  increase  was  less  than 
10  per  cent;  in  17  the  increase  was  between  10  per  cent  and  20  per  cent, 
and  in  7  the  increase  was  21  per  cent  or  more  above  the  basal.  From 
a  study  of  the  individual  experiments,  of  the  averages  of  the  various 
groups  of  patients,  or  of  the  experiments  carried  out  after  the  patients 
had  received  thyroxin,  no  consistent  parallelism  can  be  seen  between 
the  percentage  increase  in  the  systolic  blood  pressure  following  the 
injection  of  adrenalin  and  the  degree  of  over-  or  under-activity  of  the 
thjrroid  gland. 

Pulse  rate.  The  pulse  rate  increased  in  all  but  3  cases :  One  of  these 
was  a  case  of  myxedema  in  which  the  basal  metabolic  rate  was  —  40 
per  cent;  the  second,  a  case  of  Addison's  disease  in  which  the  basal 


REACTIONS    TO    SUBCUTANEOUS   INJECTION    OF   ADRENALIN         419 


metabolic  rate  was  -3  per  cent;  and  the  third,  a  case  of  mild  exoph- 
thahnic  goiter  in  a  stage  of  remission  in  which  the  basal  metabolic  rate 
was  +  9  per  cent.  Ten  cases  showed  less  than  a  10  per  cent  increase; 
all  the  rest  showed  a  greater  response.  With  an  increase  in  the  oxygen 
consumed  and  carbon  dioxid  produced  following  the  injection  of  adrena- 
lin the  circulatory  sj^stem  must  transport  larger  amounts  of  these  and 
of  other  substances.  This  can  be  accompUshed  in  two  ways :  a,  by  an 
increase  (15),  (16)  in  the  blood  flow  which  can  be  brought  about  either 
by  an  increase  in  the  number  of  beats  of  the  heart  for  each  minute,  or 
by  an  increase  in  the  volume  of  each  beat  (or  by  both,  or  by  a  large 
increase  of  one  with  a  decrease  of  the  other) ;  and  6,  by  a  unit  volume 

TABLE  4 

Summary  of  effect  of  subcutaneous  injection  of  adrenalin  chlorid  on  blood  pressure, 

pulse  rate,  and  respiration  rate  {standard  dose  of  adrenalin  chlorid  0.5  cc.) 


DIAGNOSIS 


Exophthalmic  goiter 

Adenomas  of  thyroid  with  hyperthyroidism. . 
Adenomas  of  thyroid  without  hyperthyroid- 
ism   

Colloid  goiter 

Cardiac  disease 

Neurasthenia 

Malignancy 

Pulmonary  tuberculosis 


AVERAGE 
B.  M.  R. 


per  cent 

+32 
+30 


-1 

+3 
+2 
+4 
-3 
+20 


PERCENTAGE 

INCREASE  OVER 

BASAI. 


Systolic 

blood 

pressure 


per  cent 
14 
17 

7 

3 
13 

6 

3 
18 


Pulse 


per  cent 

18 
11 

14 
17 
25 
15 
21 
6 


of  blood  carrying  a  greater  load.  Which  of  these  variable  factors  will 
predominate  is  of  course  impossible  to  predict.  Furthermore,  no 
consistent  relationship  can  be  seen  following  the  injection  of  adrenalin 
between  the  response  of  the  pulse  rate  and  the  degree  of  activity  of 
the  thyroid  gland. 

Suppkmentary  experiments.  A  second  series  of  29  experiments  was 
carried  out  in  a  manner  similar  to  that  employed  in  the  preceding  series 
except  that  the  metabolic  rates  were  not  determined  after  the  admin- 
istration of  adrenalin.  The  results  are  presented  in  a  summarized 
form  in  table  4.  As  in  the  first  series,  there  is  in  the  various  groups 
an  average  irregular  increa.se  in  both  pulse  rate  and  systolic  blood 


420  IRENE    SANDIFORD 

pressures.  We  can  discern  no  parallelism  between  the  changes  in 
pulse  rate  and  blood  pressures  and  the  degree  of  hyperthyroidism  that 
would  in  any  way  render  the  reaction  of  diagnostic  value  in  such  con- 
ditions, as  has  been  suggested  by  Goetsch  (17). 

GENERAL  DISCUSSION 

These  experiments  indicate  that  the  injection  of  adrenahn  chlorid 
produces  invariably  an  increase  in  the  rate  of  cellular  combustion 
varying  between  a  calorific  increase  of  from  4  per  cent  to  48  per  cent. 
This  increase  is  accompanied  as  a  rule  by  an  increase  in  the  ven- 
tilation rate,  respiration  rate,  number  of  heart  beats  for  each -minute, 
volume  of  each  beat,  greater  utilization  of  the  blood -carrying  power 
and  peripheral  dilatation  with  an  increased  systolic  and  decreased 
diastoHc  blood  pressure.  Not  all  these  compensatory  factors  neces- 
sarily come  into  play  in  each  instance;  as  would  be  expected,  vari- 
ous combinations  may  occur,  sometimes  one  factor,  sometimes  an- 
other factor  acting  as  the  major  compensation.  In  individual  in- 
stances it  is  impossible  to  predict  the  combination,  although  in  per- 
fectly healthy  and  well-trained  persons  such  as  those  in  the  group  of 
normal  soldiers  studied  by  Tompkins,  Sturgis  and  Wearn,  each  com- 
pensation factor  plays  its  role  so  well  and  so  easily  that  there  is  dis- 
cernible only  the  sHghtest  increase  of  any  one  factor,  while  in  the  case 
of  ill-acting  hearts  (irritable  hearts)  the  response  to  extra  demands  is 
not  smoothly  and  efficiently  accomplished.  This  is  true  also  in  any 
condition  like  hyperthyroidism  in  which  the  circulatory  system  is  more 
or  less  damaged  and  already  severely  taxed  by  its  own  increased  metab- 
olism, and  as  a  result  an  additional  load  is  not  readily  borne. 

No  relationship  was  found  in  our  experiments  between  the  intensity 
of  the  reaction  and  the  degree  of  hyper-  or  hypothyroidism.  There  is 
no  soimd  physiologic  foundation,  so  far  as  we  can  see,  for  the  assump- 
tion that  the  character  of  the  reaction  following  the  injection  of  adrenalin 
chlorid  is  indicative  of  the  activity  of  the  thyroid  gland. 

The  cause  of  the  increased  heat  production  is  unknown.  The  simi- 
larity of  the  metabolic  rate  curve  following  the  injection  of  adrenalin 
to  that  found  by  Lusk  from  a  carbohydrate  plethora  naturally  directs 
attention  to  the  possibility  that  the  increased  heat  production  is  due 
to  an  excess  of  carbohydrate  metabolites.  In  addition  there  may  be, 
however,  a  direct  chemical  stimulation  of  cellular  combustion.  In 
either  case  the  phenomenon  is  obviously  in  harmony  with  Cannon's  (18) 
"emergency  theory"  of  the  action  of  adrenalin. 


REACTIOXS    TO    SUBCUTANEOUS    INJECTION    OF    ADRENALIN         421 
SUMMARY 

1.  Forty-six  experiments  are  reported  on  the  effect  of  the  sub- 
cutaneous injection  of  adrenahn  chlorid  on  the  metabohc  rate,  pulse 
rate,  and  blood  pressure  of  patients  suffering  from  various  disorders 
of  the  ductless  glands. 

2.  A  supplementary  series  of  27  experiments  is  added  in  which  a 
studj^  was  made  of  the  effect  of  the  adrenalin  injection  on  the  pulse 
rate,  and  blood  pressure  (the  basal  metabolic  rate  being  known). 

3.  Adrenalin  chlorid  (0.5  cc.  of  1  1000)  injected  subcutaneously 
invariably  causes  an  increase  in  the  metabolic  rate.  This  increase 
is  usually  accompanied  by  an  increase  in  the  ventilation  rate,  respira- 
tion rate,  number  of  heart  beats  each  minute,  volume  of  each  beat, 
greater  utilization  of  the  blood  carrjdng  power  and  peripheral  dilatation 
with  an  increased  systolic  and  decreased  diastolic  blood  pressure. 

4.  No  relationship  was  found  between  the  intensity  of  the  adrenalin 
reaction  and  the  degree  of  hyperthj^roidism  or  hypothyroidism. 

5.  Attention  is  directed  to  the  similarity  of  the  metabolic  rate  curve 
following  the  injection  of  adrenalin  to  that  found  by  Lusk  from 
a  carbohj'drate  plethora  and  to  the  possibility  that  the  increased  heat 
production  is  due  to  an  excess  of  carbohydrate  metabolites.  It  is 
suggested  that  in  addition  there  may  be  a  direct  stimulation  of  cellular 
combustion. 

BIBLIOGRAPHY 

(1)  FucHS  AND  Roth:  Zeitschr.  f.  exper.  Path.  u.  Therap.,  1911-12,  x,  187. 

(2)  Hari:  Biochem.  Zeitschr.,  1912,  xxxviii,  23. 

(3)  Bern'stein  and  Falta:  Verhandl.  d.  Deutsch.  Kong.  f.  Innere  Med.,  1912, 

536. 

(4)  Lusk:  Proc.  Internat.  Cong.  Med.,  1913,  xiii. 

(5)  Lu.sK  AND  Riche:  Arch.  Int.  Med.,  1914,  xiii,  673. 

(6)  Tompkins,  Sturgls  and  Wearn:  Arch.  Int.  Med.,  1919,  xxiv,  269. 

(7)  La  Franca:  Zeitschr.  f.  exper.  Path.  u.  Therap.,  1909,  vi,  1. 

(8)  Wilenko:  Biochem.  Zeitschr.,  1912,  xiii,  44. 

(9)  Bernstein:  Zeitschr.  f.  exper.  Path.  u.  Therap.,  1914,  xv,  86. 

(10)  Jackson:  Journ.  Lab.  Clin.  Med.,  1916,  ii,  145. 

(11)  BooTHBY  AND  Sandiford:  Proc.  Amer.  Physiol.  Soc,  This  Journal,  1920,  li, 

200-201. 

(12)  BooTHBY  AND  Sandiford:  Laboratory  manual  on  the  technic  of  basal  meta- 

bolic rate  determinations,  Philadelphia,  Saunders,  (in  press). 

(13)  Cannon:  Bodily  changes  in  pain,  hunger,  fear  and  rage.  New  York,  Apple- 

ton,  1915. 
(14j  Lusk:  Science  of  nutrition,  Philadelphia,  Saunders,  1917. 


422  IRENE   SANDIFORD 

(15)  Boothby:  This  Journal,  1915,  xxxvii,  383. 

(16)  Boothby  and  Sandxfokd:  This  Journal,  1916,  xl,l[547. 

(17)  Gobtsch:  N.  Y.  State  Journ.  Med.,  1918,  xviii,  259. 

(18)  Caknon:  This  Journal,  1919, 1,  399. 


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